Abstract (30 lines or less) HIV-associated neurocognitive disorders (HAND) remain a concern in the US and worldwide for the nearly 40 million people living with HIV. One of the hallmark features of HAND pathogenesis is the infiltration of immune cells and viral replication in the brain. This process occurs in part due to a loss of blood-brain barrier (BBB) integrity, which results in hyperpermeability and increased immune cell extravasation. Additionally, it is well established that drugs of abuse can exacerbate HAND by augmenting blood-brain barrier (BBB) dysfunction and neuroinflammation. The mechanisms that govern BBB resilience, or lack thereof, and recovery during HIV/substance abuse remain understudied. This proposal is based on the central premise that understanding these mechanisms could identify means to speed BBB recovery, attenuate immune cell infiltration and ultimately slow the progression of HAND. We are focused on a subclass of immune cells, non-classical monocytes or patrolling monocytes, that have been identified for their unique functions in vascular maintenance and homeostasis. Patrolling monocytes have been shown to survey the luminal endothelial surface, scavenge debris and initiate vascular repair. These processes are clearly positive effects that aid in the preservation and recovery of the vasculature. However, the functions of these specialized cells have not been studied in the context of substance abuse or HIV. We will test the central hypothesis that cocaine impairs patrolling monocyte function and repair of the BBB. Additionally, we will also investigate the innovative concept that the cerebral vascular endothelium communicates the need for vascular repair through extracellular vesicles. We propose a multilateral approach that utilizes in vivo models, advanced in vitro microfluidic modeling of the BBB, and analysis of clinical samples to understand the role and function of patrolling monocytes in the context of HIV/substance abuse. Importantly, our use of advanced in vitro microfluidic modeling of the BBB with primary human cells presents the opportunity to study endothelial-immune interactions in a way that more closely mimics the human in vivo environment. Overall, the studies encompassed in this proposal will advance current knowledge regarding patrolling monocyte function, cerebral endothelial-immune interactions, and establish a novel mechanism by which drugs of abuse contributes to HAND.